This family consists of type III secretion system (T3SS) stator protein, previously known as nodulation protein NolV, from different Rhizobium species [
]. The function of this family is unclear, however, it has been suggested that T3SS stator protein is a component of the T3SS, which is used to inject bacterial effector proteins into eukaryotic host cells.
This entry represents a five-bladed beta propellor domain of Tachylectin 2. It consists of five four-stranded antiparallel β-sheets are arranged around a water channel. Tachylectin 2 binds specifically to N-acetylglucosamine and N-acetylgalactosamine and is part of the organism's immunity host defense systems [
]. Tachylectin 2 has five binding sites (one on each β-sheet)for substrate carbohydrate recognition; by combining specificity for N-acetylcarbohydrates with a high density of ligand binding sites, tachylectin 2 is able to recognise foreign sugars.
Pancreatic ribonucleases (RNaseA) are pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles [
]. Specifically, the enzymes are involved in endonucleolytic cleavage of 3'-phosphomononucleotides and 3'-phosphooligonucleotides ending in C-P or U-P with 2',3'-cyclic phosphate intermediates. Ribonuclease can unwind the DNA helix by complexing with single-stranded DNA; the complex arises by an extended multi-site cation-anion interaction between lysine and arginine residues of the enzyme and phosphate groups of the nucleotides. Other proteins belonging to the pancreatic RNAse family include: bovine seminal vesicle and brain ribonucleases; kidney non-secretory ribonucleases []; liver-type ribonucleases []; angiogenin, which induces vascularisation of normal and malignant tissues; eosinophil cationic protein [], a cytotoxin and helminthotoxin with ribonuclease activity; and frog liver ribonuclease and frog sialic acid-binding lectin. The sequence of pancreatic RNases contains four conserved disulphide bonds and three amino acid residues involved in the catalytic activity.This entry represents a domain superfamily found in Ribonuclease A. Its structure is an alpha+beta fold with long curved beta sheet and three helices.
The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimers within all eukaryotic cells [
,
]. These are structurally similar phospho-binding proteins that regulate multiple signaling pathways []. There is a high degree of sequence identity and conservation between all the 14-3-3 isotypes, particularly in the regions which form the dimer interface or line the central ligand binding channel of the dimeric molecule. Each 14-3-3 protein sequence can be roughly divided into three sections: a divergent amino terminus, the conserved core region and a divergent carboxyl terminus. The conserved middle core region of the 14-3-3s encodes an amphipathic groove that forms the main functional domain, a cradle for interacting with client proteins. The monomer consists of nine helices organised in an antiparallel manner, forming an L-shaped structure. The interior of the L-structure is composed of four helices: H3 and H5, which contain many charged and polar amino acids, and H7 and H9, which contain hydrophobic amino acids. These four helices form the concave amphipathic groove that interacts with target peptides.The 14-3-3 proteins mainly bind proteins containing phosphothreonine or phosphoserine motifs, however exceptions to this rule do exist. Extensive investigation of the 14-3-3 binding site of the mammalian serine/threonine kinase Raf-1 has produced a consensus sequence for 14-3-3-binding, RSxpSxP (in the single-letter amino-acid code, where x denotes any amino acid and p indicates that the next residue is phosphorylated). The 14-3-3 proteins appear to effect intracellular signalling in one of three ways - by direct regulation of the catalytic activity of the bound protein, by regulating interactions between the bound protein and other molecules in the cell by sequestration or modification or by controlling the subcellular localisation of the bound ligand. Proteins appear to initially bind to a single dominant site and then subsequently to many, much weaker secondary interaction sites. The 14-3-3 dimer is capable of changing the conformation of its bound ligand whilst itself undergoing minimal structural alteration.
This entry represents the N-terminal domain of the axin interactor, dorsalization-associated protein (AIDA) superfamily [
]. AIDA acts as a ventralizing factor during embryogenesis. It inhibits axin-mediated JNK activation by binding axin and disrupting axin homodimerization. This in turn antagonizes a Wnt/beta-catenin-independent dorsalization pathway activated by axin/JNK-signaling []. The core structure of the AIDA N-terminal domain consists of four helices arranged in a close or partly open bundle fold with left-handed twist going up-and-down.
This entry includes transthyretin that is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. However, most of the sequences listed in this entry do not bind thyroid hormones. They are actually enzymes of the purine catabolism that catalyse the conversion of 5-hydroxyisourate (HIU) to OHCU [
,
]. HIU hydrolysis is the original function of the family and is conserved from bacteria to mammals; transthyretins arose by gene duplications in the vertebrate lineage [,
]. HIUases are distinguished in the alignment from the conserved C-terminal YRGS sequence.Transthyretin (formerly prealbumin) is one of 3 thyroid hormone-binding proteins found in the blood of vertebrates [
]. It is produced in the liver and circulates in the bloodstream, where it binds retinol and thyroxine (T4) []. It differs from the other 2 hormone-binding proteins (T4-binding globulin and albumin) in 3 distinct ways: (1) the gene is expressed at a high rate in the brain choroid plexus; (2) it is enriched in cerebrospinal fluid; and (3) no genetically caused absence has been observed, suggesting an essential role in brain function, distinct from that played in the bloodstream []. The protein consists of around 130 amino acids, which assemble as a homotetramer that contains an internal channel in which T4 is bound. Within this complex, T4 appears to be transported across the blood-brain barrier, where, in the choroid plexus, the hormone stimulates further synthesis of transthyretin. The protein then diffuses back into the bloodstream, where it binds T4 for transport back to the brain []. Structurally, it consists of a sandwich fold with seven strands arranged in two sheets and a greek-key topology.
The Streptomyces family of bacteria produce a number of proteinase inhibitors, which belong to MEROPS inhibitor family I16, clan IY. They are characterised by their strong activity towards subtilisin (MEROPS peptidase family S8,
) and are collectively known as Streptomyces subtilisin inhibitors (SSI). Some SSI also inhibit trypsin, chymotrypsin (MEROPS peptidase family S1,
) and griselysin (MEROPS peptidase family M4,
) [
]. Mutation of the active site residue can influenceinhibition specificity [
].SSI is a homodimer, each monomer containing 2 anti-parallel β-sheets
and 2 short α-helices. Protease binding induces the widening of a channel-like structure, in whichhydrophobic side-chains are sandwiched between 2 lobes [
]. Loss of the C-terminal tetrapeptideVFAF drastically reduces the inhibitory effect of the proteins when there is less than one molecule of
inhibitor present per molecule of enzyme. This implies that the tetrapeptide is neccessary to maintain thecorrect 3D fold [
]. Structural similarities between the primary and secondary contact loops of SSI,and the ovomucoid and pancreatic secretory trypsin inhibitor family suggest evolution of the 2 families from
a common ancestor [].
Glucocorticoid modulatory element-binding protein 1/2
Type:
Family
Description:
Glucocorticoid modulatory element-binding (GMEB) proteins 1 and 2 are homologous sequences that form a heteromeric complex that binds to glucocorticoid modulatory elements and increases sensitivity to low concentrations of glucocorticoids [
,
]. The GMEB1/2 complex is also an essential auxiliary factor for the replication of parvoviruses, critically regulating the viral nickase during infection []. GMEB1 has been shown to inhibit caspase, preventing hypoxia- and oxidative stress-induced neuronal apoptosis []. This entry also includes Transcription regulator spe-44 from Caenorhabditis elegans, a transcription factor that controls spermatogenesis and sperm cell fate by regulation of sperm gene expression, highly similar to the mammalian GMEB1/2 [].
This entry represents uroplakin-3 and related proteins.Uroplakins (UPs) are a family of proteins that associate with each other to form plaques on the apical surface of the urothelium, the pseudo-stratified epithelium lining the urinary tract from renal pelvis to the bladder outlet [
,
]. UPs are classified into 3 types: UPIa and UPIb, UPII, and UPIIIa and IIIb. UPIs are tetraspanins that have four transmembrane domains separating one large and one small extracellular domain while UPII and UPIIIs are single-pass transmembrane proteins. UPIa and UPIb form specific heterodimers with UPII and UPIII, respectively, which allows them to exit the endoplasmatic rediculum. UPII/UPIa and UPIIIs/UPIb form heterotetramers and six of these tetramers form the 16nm particle, seen in the hexagonal array of the asymmetric unit membrane, which is believed to form a urinary tract barrier []. Uroplakins are also believed to play a role during urinary tract morphogenesis [,
].
Insulin-like Growth Factor Binding Proteins (IGFBP) are a group of vertebrate secreted proteins, which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGFs. The IGFBP family has six distinct subgroups, IGFBP-1 through 6, based on conservation of gene (intron-exon) organisation, structural similarity, and binding affinity for IGFs. Across species, IGFBP-5 exhibits the most sequence conservation, while IGFBP-6 exhibits the least sequence conservation. The IGFBPs contain inhibitor domain homologues, which are related to MEROPS protease inhibitor family I31 (equistatin, clan IX). All IGFBPs share a common domain architecture (
:
). While the N-terminal (
, IGF binding protein domain), and the C-terminal (
, thyroglobulin type-1 repeat) domains are conserved across vertebrate species, the mid-region is highly variable with respect to protease cleavage sites and phosphorylation and glycosylation sites. IGFBPs contain 16-18 conserved cysteines located in the N-terminal and the C-terminal regions, which form 8-9 disulphide bonds [
]. As demonstrated for human IGFBP-5, the N terminus is the primary binding site for IGF. This region, comprised of Val49, Tyr50, Pro62 and Lys68-Leu75, forms a hydrophobic patch on the surface of the protein [
]. The C terminus is also required for high affinity IGF binding, as well as for binding to the extracellular matrix [] and for nuclear translocation [,
] of IGFBP-3 and -5. IGFBPs are unusually pleiotropic molecules. Like other binding proteins, IGFBP can prolong the half-life of IGFs via high affinity binding of the ligands. In addition to functioning as simple carrier proteins, serum IGFBPs also serve to regulate the endocrine and paracrine/autocrine actions of IGF by modulating the IGF available to bind to signalling IGF-I receptors [
,
]. Furthermore, IGFBPs can function as growth modulators independent of IGFs. For example, IGFBP-5 stimulates markers of bone formation in osteoblasts lacking functional IGFs []. The binding of IGFBP to its putative receptor on the cell membrane may stimulate the signalling pathway independent of an IGF receptor, to mediate the effects of IGFBPs in certain target cell types. IGFBP-1 and -2, but not other IGFBPs, contain a C-terminal Arg-Gly-Asp integrin-binding motif. Thus, IGFBP-1 can also stimulate cell migration of CHO and human trophoblast cells through an action mediated by alpha 5 beta 1 integrin []. Finally, IGFBPs transported into the nucleus (via the nuclear localisation signal) may also exert IGF-independent effects by transcriptional activation of genes.This entry represents insulin-like growth factors (IGF-I and IGF-II), which bind to specific binding proteins in extracellular fluids with high affinity [
,
,
]. These IGF-binding proteins (IGFBP) prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cells culture. They seem to alter the interaction of IGFs with their cell surface receptors. There are at least six different IGFBPs and they are structurally related. The following growth-factor inducible proteins are structurally related to IGFBPs and could function as growth-factor binding proteins [
,
], mouse protein cyr61 and its probable chicken homologue, protein CEF-10; human connective tissue growth factor (CTGF) and its mouse homologue, protein FISP-12; and vertebrate protein NOV.
This entry includes synaptonemal complex protein 2 (SYCP2) and synaptonemal complex protein 2-like (SYCP2L).SYCP2 is one of the major components of the transverse filaments of the synaptonemal complex. Synaptonemal complexes are structures that are formed between homologous chromosomes during meiotic prophase [
].SYCP2L has partial sequence homology to a SYCP2 and is the major component of nucleolar cortical skeleton in Xenopus oocytes [
]. In humans, SYCP2L promotes primordial oocytes survival, thus being associated with age at natural menopause (ANM) [].
Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium,
nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds [
,
,
]. The metallothionein superfamily comprises all polypeptides that resemble equine renal metallothionein in several respects, e.g. low molecular
weight; high metal content; amino acid composition with high Cys and low aromatic residue content; unique sequence with characteristic distribution of cysteines, and spectroscopic manifestations
indicative of metal thiolate clusters. A MT family subsumes MTs that share particular sequence-specific features and are thought to be evolutionarily related. Fifteen MT families have been characterised,
each family being identified by its number and its taxonomic range.Fungi-IV (family 11) MTs are
proteins of about 55-56 residues, with 9 conserved cysteines. Its members are recognised by the sequence pattern C-X-K-C-x-C-x(2)-C-K-C. The taxonomic range of the members extends to ascomycotina.
The protein contains a number of unusual histidine and phenylalanine residues conserved in the N-terminal part of the sequence. This fragment does not contain any Cys. The protein binds to copper ions.
Regulated endocrine-specific protein 18 (RESP18) is a major glucocorticoid-responsive protein that is mainly distributed in the peripheral endocrine and neuroendocrine tissues [
]. The protein shares sequence homology with the luminal region of IA-2, a dense core vesicle (DCV) transmembrane protein involved in insulin secretion [].The function of RESP18 is unknown, but it may may play an important regulatory role in corticotrophs and peptidergic neurons [
].
Janus kinase and microtubule interacting proteins (JAKMIPs) are predominantly expressed in neural tissues and lymphoid organs. Three family members have been identified, termed JAKMIP1-3. They contain an N-terminal region that targets the protein to microtubule polymers and a C-terminal region that is able to associate with Janus kinase (Jak) family members, such as Tyk2 or Jak1 [
]. The proteins may have a role in Jak signalling and regulation of microtubule cytoskeleton rearrangements.JAKMIP1 has also been shown to interact with GABA(B) receptor R1 subunits [
], and may be involved in microtubule-dependent transport of the GABA-B receptor [].
Anaerobic ribonucleoside-triphosphate reductase activating protein
Type:
Family
Description:
This enzyme is a member of the radical-SAM family. It is often gene clustered with the class III (anaerobic) ribonucleotide triphosphate reductase (NrdD,
) and presumably fulfils the identical function as NrdG [
,
], which utilises S-adenosyl methionine, an iron-sulphur cluster and a reductant (dihydroflavodoxin) to produce a glycine-centred radical in NrdD [].
This domain superfamily was determined from the crystal structure of a protein of unknown function from Rhizobium meliloti (Sinorhizobium meliloti). The domain is found in a family, which consists of several short bacterial proteins of around 100 residues in length. The function of this domain is unknown. Structurally, this domain is multihelical, it is composed of intertwined homodimer where there are four core helices in each subunits.
D-aminopeptidase (
) is a dimeric enzyme with each monomer being composed of three domains. Domain B is organised to form a beta barrel made up of eight antiparallel beta strands. It is connected to domain A, the catalytic domain, by an eight-residue sequence, and also interacts with both domains A and C via non-covalent bonds. Domain B probably functions in maintaining domain C in a good position to interact with the catalytic domain [
]. This domain is found in peptidases that belong to MEROPS peptidase family S12 (D-Ala-D-Ala carboxypeptidase B family, clan ME).
Diphtheria toxin (
) is a 58kDa protein secreted by lysogenic strains of Corynebacterium diphtheriae. The toxin causes the disease diphtheria in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis [
]. The mechanism of inhibition involves transfer of the ADP-ribose group of NAD to elongation factor-2 (EF-2), rendering EF-2 inactive. The catalysed reaction is as follows: NAD++ peptide diphthamide = nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide
The crystal structure of the diphtheria toxin homodimer has been determined to 2.5A resolution []. The structure reveals a Y-shaped molecule of 3 domains, a catalytic domain (fragment A), whose fold is of the α+β type; a transmembrane (TM) domain, which consists of 9 α-helices, 2 pairs of which may participate in pH-triggered membrane insertion and translocation; and a receptor-binding domain, which forms a flattened β-barrel with a jelly-roll-like topology []. The TM- and receptor binding-domains together constitute fragment B.This entry represents the translocation domain (also known as the T domain) found in the middle of the Diphtheria toxin protein. The T domain has a multi-helical globin-like fold with two additional helices at N-termini, but which has no counterpart to the first globin helix. This domain is thought to unfold in the membrane [
]. pH-induced conformational change in the T domain triggers insertion into the endosomal membrane and facilitates the transfer of the catalytic domain into the cytoplasm [,
].
Members of this family are encoded by archaeal flagellar operons, and are therefore predicted to be involved in archaeal flagellar assembly, but their specific role is unknown [
]. In several archaea, the flagellin genes are followed immediately by the genes encoding flagellar accessory proteins flaCDEFGHIJ. They may have a role in translocation, secretion, or assembly of the flagellum. FlaC has been shown to be membrane-associated.Archaeal flagella, found in all the main groupings of archaea, differ from eubacterial flagella in both structure and composition, although some archaeal flagellar proteins show similarity to the eubacterial proteins involved in the pilus biogenesis/type II and IV secretory pathways [
,
,
,
,
].
These proteins, which are annotated as putative nucleotidases, contain a domain that is distantly related to HAD-like hydrolase domain, and belong to the SCOP HAD-like hydrolase domain superfamily.
Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. There are two classes of amine oxidases: flavin-containing (
) and copper-containing (
). Copper-containing AO act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor [
]: RCH
2NH
2+ H
2O + O
2= RCHO + NH
3+ H
2O
2Copper-containing amine oxidases are found in bacteria, fungi, plants and animals. In prokaryotes, the enzyme enables various amine substrates to be used as sources of carbon and nitrogen [
,
]. In eukaryotes they have a broader range of functions, including cell differentiation and growth, wound healing, detoxification and cell signalling [].The copper amine oxidases occur as mushroom-shaped homodimers of 70-95kDa, each monomer containing a copper ion and a covalently bound redox cofactor, topaquinone (TPQ). TPQ is formed by post-translational modification of a conserved tyrosine residue. The copper ion is coordinated with three histidine residues and two water molecules in a distorted square pyramidal geometry, and has a dual function in catalysis and TPQ biogenesis. The catalytic domain is the largest of the 3-4 domains found in copper amine oxidases, and consists of a beta sandwich of 18 strands in two sheets. The active site is buried and requires a conformational change to allow the substrate access. The two N-terminal domains share a common structural fold, its core consisting of a five-stranded antiparallel β-sheet twisted around an α-helix. The D1 domains from the two subunits comprise the stalk, of the mushroom-shaped dimer, and interact with each other but do not pack tightly against each other [
,
]. This entry represents a domain found at the N-terminal of certain copper amine oxidases, as well as in related proteins such as cell wall hydrolase and N-acetylmuramoyl-L-alanine amidase. This domain consists of a five-stranded antiparallel β-sheet twisted around an alpha helix [
,
].
Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [
]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [].The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (
), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (
) to charge a tRNA with glutamate, glutamyl-tRNA reductase (
) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (
) to catalyse a transamination reaction to produce ALA.
The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase,
) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase,
) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (
) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.
Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (
). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (
) [
].Porphobilinogen deaminase (also known as hydroxymethylbilane synthase,
) functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses the polymerisation of four PBG molecules into the tetrapyrrole structure, preuroporphyrinogen, with the concomitant release of four molecules of ammonia. This enzyme uses a unique dipyrro-methane cofactor made from two molecules of PBG, which is covalently attached to a cysteine side chain. The tetrapyrrole product is synthesized in an ordered, sequential fashion, by initial attachment of the first pyrrole unit (ring A) to the cofactor, followed by subsequent additions of the remaining pyrrole units (rings B, C, D) to the growing pyrrole chain [
]. The link between the pyrrole ring and the cofactor is broken once all the pyrroles have been added. This enzyme is folded into three distinct domains that enclose a single, large active site that makes use of an aspartic acid as its one essential catalytic residue, acting as a general acid/base during catalysis [,
]. A deficiency of hydroxymethylbilane synthase is implicated in the neuropathic disease, Acute Intermittent Porphyria (AIP) []. This entry represents the C-terminal domain superfamily of porphobilinogen deaminase, an enzyme involved in tetrapyrrole biosynthesis. The structure of this alpha/beta domain consists of α-β(3)-alpha in two layers [
]. Porphobilinogen deaminase has a three-domain structure. Domains 1 (N-terminal) and 2 are duplications with the same structure, resembling the transferrins and periplasmic binding proteins. The dipyrromethane cofactor is covalently linked to domain 3 (C-terminal), but is bound by extensive salt-bridges and hydrogen-bonds within the cleft between domains 1 and 2, at a position corresponding to the binding sites for small-molecule ligands in the analogous proteins []. The enzyme has a single catalytic site, and the flexibility between domains is thought to aid elongation of the polypyrrole product in the active-site cleft of the enzyme.
Histone-lysine N-methyltransferase, H3 lysine-37 specific
Type:
Family
Description:
This entry includes SET7, an histone lysine methyltransferase that specifically mono-, di-, and trimethylates 'Lys-37' of histone H3 [
]. In S. pombe, SET7 regulates sporulation [].
The members of this family are all similar to chloramphenicol 3-O phosphotransferase (CPT,
) expressed by Streptomyces venezuelae. Chloramphenicol (Cm) is a metabolite produced by this bacterium that can inhibit ribosomal peptidyl transferase activity and therefore protein production. By transferring a phosphate group to the C-3 hydroxyl group of Cm, CPT inactivates this potentially lethal metabolite [
,
].
This domain found in N terminus of ATP:guanido phosphotransferases contains an all-alpha fold consisting of an irregular array of 6 short helices [
].ATP:guanido phosphotransferases are a family of structurally and functionally related enzymes [
,
] that reversibly catalyse the transfer of phosphate between ATP and various phosphogens. The enzymes belonging to this family include:Glycocyamine kinase (
), which catalyses the transfer of phosphate from ATP to guanidoacetate.
Arginine kinase (
), which catalyses the transfer of phosphate from ATP to arginine.
Taurocyamine kinase (
), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to taurocyamine.
Lombricine kinase (
), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to lombricine.
Smc74, a cercaria-specific enzyme from Schistosoma mansoni[
].Creatine kinase (
) (CK) [
,
], which catalyses the reversible transfer of high energy phosphate from ATP to creatine, generating phosphocreatine and ADP. Creatine kinase plays an important role in energy metabolism of vertebrates. There are at least four different, but very closely related, forms of CK. Two isozymes, M (muscle) and B (brain), are cytosolic, while the other two are mitochondrial. In sea urchins there is a flagellar isozyme, which consists of the triplication of a CK-domain. A cysteine residue is implicated in the catalytic activity of these enzymes and the region around this active site residue is highly conserved.
Bacterial proteins GreA and GreB are necessary for efficient RNA polymerase transcription elongation past template-encoded arresting sites. Arresting sites in DNA have the property of trapping a certain fraction of elongating RNA polymerases that pass through, resulting in locked DNA/RNA/ polymerase ternary complexes. Cleavage of the nascent transcript by cleavage factors, such as GreA or GreB, allows the resumption of elongation from the new 3' terminus [
,
]. Escherichia coli GreA and GreB are sequence homologues and have homologues in every known bacterial genome []. GreA induces cleavage two or three nucleotides behind the terminus and can only prevent the formation of arrested complexes while greB releases longer sequences up to eighteen nucleotides in length and can rescue preexisting arrested complexes. These functional differences correlate with a distinctive structural feature, the distribution of positively charged residues on one face of the N-terminal coiled coil. Remarkably, despite close functional similarity, the prokaryotic Gre factors have no sequence or structural similarity with eukaryotic TFIIS.
This entry represents the N-terminal domain of archaeal pilins, which play important roles in surface adhesion. Sequences covered by this domain are not mixed up with sequences having such an extremely high sequence conservation as described in [
].
CheR proteins are part of the chemotaxis signaling mechanism in bacteria. Flagellated bacteria swim towards favourable chemicals and away from deleterious ones. Sensing of chemoeffector gradients involves chemotaxis receptors, transmembrane (TM) proteins that detect stimuli through their periplasmic domains and transduce the signals via their cytoplasmic domains [
]. Signalling outputs from these receptors are influenced both by the binding of the chemoeffector ligand to their periplasmic domains and by methylation of specific glutamate residues on their cytoplasmic domains. Methylation is catalysed by CheR, an S-adenosylmethionine-dependent methyltransferase [], which reversibly methylates specific glutamate residues within a coiled coil region, to form gamma-glutamyl methyl ester residues [
,
].The structure of the Salmonella typhimurium chemotaxis receptor methyltransferase CheR, bound to S-adenosylhomocysteine, has been determined to a resolution of 2.0 A [
]. The structure reveals CheR to be a two-domain protein, with a smaller N-terminal helical domain linked via a single polypeptide connection to a larger C-terminal alpha/beta domain. The C-terminal domain has the characteristics of a nucleotide-binding fold, with an insertion of a small anti-parallel β-sheet subdomain. The S-adenosylhomocysteine-binding site is formed mainly by the large domain, with contributions from residues within the N-terminal domain and the linker region [].
This group of sequences is similar to a region of the dendritic cell-specific transmembrane protein (DC-STAMP,
). This is thought to be a novel receptor protein that shares no identity with other multimembrane-spanning proteins [
]. It is thought to have seven putative transmembrane regions [], two of which are found in the region featured in this family. DC-STAMP is also described as having potential N-linked glycosylation sites and a potential phosphorylation site for PKC [], but these are not conserved.
This domain is found in a family of proteins that include a hypothetical protein from Pyrococcus horikoshii, which has no known function. It contains six alpha helices and eight beta strands and is thought to be monomeric.
YozE-like is a family of Firmicute proteins that carries a four-helix motif similar to sterile alpha motif (SAM) domains. The family is suggested to fall into two subfamilies, possibly with differing functions based on the different surface charges on the three structural representatives, YozE, MW0776 and MW1311. This function is not yet known, although it is likely to involve binding to DNA [
].
This domain is found in a superfamily of proteins, which have no known function. Its structure is composed of three helices arranged in a close bundle fold with left-handed twist going up-and-down and a mirror topology to the spectrin-like fold.
Beta-lactamase catalyses the opening and hydrolysis of the beta-lactam ring of beta-lactam antibiotics such as penicillins and cephalosporins. There are four groups, classed A, B, C and D according to sequence, substrate specificity, and kinetic behaviour. Class A (penicillinase-type) is the most common [
]. The genes for class A beta-lactamases are widely distributed in bacteria, frequently located on transmissible plasmids in Gram-negative organisms, although an equivalent chromosomal gene has been found in a few species []. Class A, C and D beta-lactamases are serine-utilising hydrolases, while class B enzymes utilise a catalytic zinc centre instead. The 3 classes of serine beta-lactamase are evolutionarily related and belong to a superfamily that also includes DD-peptidases and other penicillin-binding proteins []. All these proteins contain an S-x-x-K motif, the Ser being the active site residue []. Although clearly related, however, the sequences of the 3 classes of serine beta-lactamases vary considerably outside the active site.This entry represents the Group 2 beta-lactamases, which correspond to the penicillinases and cephalosporinases, which are inhibited by clavulanic acid. They corresponding to the molecular classes A and D reflecting the original TEM and SHV genes. However, because of the increasing number of TEM and SHV derived beta-lactamases, they have been divided into two subclasses, 2a and 2b: The 2a subgroup contains just penicillinases.The 2b subgroup contains broad spectrum beta-lactamases, meaning that they are capable of inactivating penicillins and cephalosporins at the same rate. Furthermore, new subgroups were segregated from subgroup 2b based on their activity against certain antibiotics and resistance to clavulanic acid.Molecular Class D or A Subgroup 2d enzymes inactivate cloxacillin more than benzylpenicillin, with some activity against carbenicillin; these enzymes are poorly inhibited by clavulanic acid, and some of them are extended spectrum beta-lactamases (ESBLs).The class A and D beta-lactamases belong to MEROPS peptidase family S11 (D-Ala-D-Ala carboxypeptidase A family, clan SE).
This domain superfamily contains three alpha helices and six beta strands. It is found in a protein that is produced from gene PA1123 of Pseudomonas. The protein PA1123 appears to be present in the biofilm layer and may be a lipoprotein.
Dip2 proteins show sequence similarity to other members of the adenylate forming enzyme family, including insect luciferase, acetyl CoA ligases and the adenylation domain of nonribosomal peptide synthetases (NRPS) [
,
,
,
]. However, its function may have diverged from other members of the superfamily. In mouse embryo, Dip2 homologue A plays an important role in the development of both vertebrate and invertebrate nervous systems. Dip2A appears to regulate cell growth and the arrangement of cells in organs. Biochemically, Dip2A functions as a receptor of FSTL1, an extracellular glycoprotein, and may play a role as a cardiovascular protective agent [,
].According to bioinformatics analysis DIP2A is a type I receptor molecule with three domains from the N to the C terminus: the DNA methyltransferase 1 associated protein (DMAP)-binding domain, CaiC, and adenosine monophosphate (AMP)-binding domain. This entry corresponds to the CaiC domain of Dip2. The CaiC domain also binds AMP and is found in acyl CoA synthetases and AMP-acid ligases that are involved in lipid metabolism, secondary metabolite biosynthesis, transport and catabolism [
].
Protein of unknown function DUF1269, membrane associated
Type:
Family
Description:
There are currently no experimental data for members of this group or their homologues. However, these proteins are predicted to contain two or more transmembrane segments.
This family consists of several Chordopoxvirus E11 proteins. The E11 gene of vaccinia virus encodes a 15kDa polypeptide. Mutations in the E11 gene makes the virus temperature-sensitive due to either the fact that virus infectivity requires a threshold level of active E11 protein or that E11 function is conditionally essential [
].
This entry includes a group of fungal proteins that are involved in cell wall biosynthesis, including Smi1 from S. cerevisiae and Cot2 from Neurospora crassa. Smi1 (also known as Knr4) is involved in the regulation of cell wall assembly and 1,3-beta-glucan synthesis, possibly through the transcriptional regulation of cell wall glucan and chitin synthesis [
,
]. Cot2 is required for (1,3) beta-glucan synthase activity and cell wall formation [].
Bacillus subtilis YabN is a fusion of an N-terminal TP-methylase and a C-terminal MazG-type nucleotide pyrophosphohydrolase domain. MazG-like NTP-PPases have been implicated in house-cleaning functions such as degrading abnormal (d)NTPs [
]. TP-methylases use S-AdoMet (S-adenosyl-L-methionine or SAM) in the methylation of diverse substrates. Most members catalyze various methylation steps in cobalamin (vitamin B12) biosynthesis, other members like Diphthine synthase and Ribosomal RNA small subunit methyltransferase I (RsmI) act on other substrates (). The specific function of YabN's TP-methylase domain is not known.
This entry represents the guanylin family. Its members include guanylate cyclase activator 2A and 2B. They are endogenous activators of intestinal guanylate cyclases. Guanylin, a 15-amino-acid peptide, is an endogenous ligand of the intestinal receptor guanylate cyclase-C, known as STaR [
,
]. Upon receptor binding, guanylin increases the intracellular concentration of cGMP, it induces chloride secretion and decreases intestinal fluid absorption, ultimately causing diarrhoea []. The peptide stimulates the enzyme through the same receptor binding region as the heat-stable enterotoxins [].
Growth arrest and DNA damage-inducible protein GADD45
Type:
Family
Description:
The growth arrest and DNA damage GADD45 proteins, which include GADD45A, GADD45B , and GADD45G, are implicated as stress sensors that modulate the response of mammalian cells to genotoxic/physiological stress, and modulate tumor formation [
,
,
]. GADD45 proteins interact with a number of other proteins implicated in stress responses, including PCNA, p21, Cdc2/CyclinB1, MEKK4, and p38 kinase. GADD45 stimulates DNA excision repair in vitro and inhibits the entry of cells into S phase during the cell cycle.
Bombesin-like peptides comprise a large family of peptides which were initially isolated from amphibian skin, where they stimulate smooth muscle contraction. They were later found to be widely distributed in mammalian neural and endocrine cells. The amphibian peptides which belong to this family are currently classified into three subfamilies [,
]; the Bombesin group, which includes bombesin and alytesin; the Ranatensin group, which includes ranatensins, litorin, and Rohdei litorin; and the Phyllolitorin group, which includes Leu(8)- and Phe(8)-phyllolitorins. In mammals and birds two categories of bombesin-like peptides are known [,
], gastrin-releasing peptide (GRP), which stimulates the release of gastrin as well as other gastrointestinal hormones, and neuromedin B (NMB), a neuropeptide that regulates exocrine and endocrine secretions, smooth muscle contraction, saciety, blood pressure, blood glucose, body temperature, and it is thought to play a role in reproduction and in different behavioral responses like stress or fear [,
,
]. Bombesin-like peptides, like many other active peptides, are synthesized as larger protein precursors that are enzymatically converted to their mature forms. The final peptides are eight to fourteen residues long.
Cecropins [
,
,
] are potent antibacterial proteins that constitute a main part of the cell-free immunity of insects. Cecropins are small proteins of about 35 amino acid
residues active against both Gram-positive and Gram-negative bacteria. They seem to exert a lytic action on bacterial membranes. Cecropins have been given various names, including bactericidin, lepidopteran and sarcotoxin. All of these peptides are structurally related.
This entry also includes the antibacterial protein andropin. The andropin gene is closely linked to the cecropin gene cluster of Drosophila melanogaster [,
]
Cecropins [
,
,
] are potent antibacterial proteins that constitute a main part of the cell-free immunity of insects. Cecropins are small proteins of about 35 amino acid
residues active against both Gram-positive and Gram-negative bacteria. They seem to exert a lytic action on bacterial membranes. Cecropins have been given various names, including bactericidin, lepidopteran and sarcotoxin. All of these peptides are structurally related.
This entry represents cecropins from insects.
This entry represents uroplakin-3a. Defects in uroplakin-3a are a cause of renal adysplasia, a condition in which one or both kidneys are absent at birth [
,
].Uroplakins (UPs) are a family of proteins that associate with each other to form plaques on the apical surface of the urothelium, the pseudo-stratified epithelium lining the urinary tract from renal pelvis to the bladder outlet [
,
]. UPs are classified into 3 types: UPIa and UPIb, UPII, and UPIIIa and IIIb. UPIs are tetraspanins that have four transmembrane domains separating one large and one small extracellular domain while UPII and UPIIIs are single-pass transmembrane proteins. UPIa and UPIb form specific heterodimers with UPII and UPIII, respectively, which allows them to exit the endoplasmatic rediculum. UPII/UPIa and UPIIIs/UPIb form heterotetramers and six of these tetramers form the 16nm particle, seen in the hexagonal array of the asymmetric unit membrane, which is believed to form a urinary tract barrier []. Uroplakins are also believed to play a role during urinary tract morphogenesis [,
].
Bromelain inhibitor VI is a double-chain inhibitor consisting of an 11-residue and a 41-residue chain. This protein is the 41-residue heavy chain which is joined to the 11-residue chain by disulphide bonds [
]. The inhibitor acts to inhibit the cysteine proteinase bromelain.
Archaeal DNA polymerase II (Pol II, or Pol D) is heterodimeric, containing a DP1 small subunit, and a DP2 large subunit, the latter acting as the catalytic subunit. This entry represents the DP1 small subunit, which shows sequence similarity with the small subunit of eukaryotic DNA polymerase delta; a homologue of this protein has not been found in bacteria. Archaeal Pol II possesses an excellent primer extension ability, but may require accessory proteins to perform all its functions [
].
Radiation-inducible immediate-early gene IEX-1 is a protein that in humans is encoded by the IER3 gene. The protein is involved in cell proliferation and survival, including the protection of cells from TNF-induced apoptosis [
]. It is rapidly induced by growth factors, viral infections or chemical carcinogens [].IEX-1 has a dual role in extracellular signal-regulated kinase (ERK) signalling. Upon phosphorylation by ERK, IEX-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, by binding to active ERK, IEX-1 potentiates ERK activation in response to various growth factors [,
].
Calcium-binding and coiled-coil domain-containing protein 1 (Calcoco1) from Mus musculus (
) binds to a highly conserved N-terminal domain of p160 coactivators, such as GRIP1 (
), and thus enhances transcriptional activation by a number of nuclear receptors. Calcoco1 has a central coiled-coil region with three leucine zipper motifs, which is required for its interaction with GRIP1 and may regulate the autonomous transcriptional activation activity of the C-terminal region [
].
This family consists of several roughex (RUX) proteins specific to Drosophila species. Roughex can influence the intracellular distribution of cyclin A and is therefore defined as a distinct and specialised cell cycle inhibitor for cyclin A-dependent kinase activity [
]. Rux is though to regulate the metaphase to anaphase transition during development [].
This entry represents a proteobacterial histidine utilization repressor. It is usually found clustered with the enzymes HutUHIG so that it can regulate its own expression as well. A number of species have several paralogs and may fine-tune the regulation according to levels of degradation intermediates such as urocanate. This family belongs to the larger GntR family of transcriptional regulators.
The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) [
,
] is a major carbohydrate transport system in bacteria. The PTS catalyzes the phosphorylation of incoming sugar substrates concomitant with their translocation across the cell membrane. The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred to enzyme-I (EI) of PTS which in turn transfers it to a phosphoryl carrier protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease which consists of at least three structurally distinct domains (IIA, IIB, and IIC) [] which can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).The first domain (IIA) carries the first permease-specific phoshorylation site, a histidine, which is phosphorylated by phospho-HPr. The second domain (IIB) is phosphorylated by phospho-IIA on a cysteinyl or histidyl residue, depending on the permease. Finally, the phosphoryl group is transferred from the IIB domain to the sugar substrate in a process catalyzed by the IIC domain; this process is coupled to the transmembrane transport of the sugar.Several PTS permease families are currently recognised, namely, the (i) glucose (including glucoside), (ii) fructose (including mannitol), (iii) lactose (including N,N-diacetylchitobiose), (iv) galactitol, (v) glucitol, (vi) mannose, and (vii) l-ascorbate families [
].This entry represents the component IIB of the glucose family of PTS systems (type 1). The structure of this domain has a homing endonuclease-like fold, which is composed of an α-β(2)-α-β(2)-alpha fold arranged into two layers (alpha/beta) with antiparallel sheet.
This entry represents the component of bacteriochlorophyll synthetase responsible for reduction of the B-ring pendant ethylene (4-vinyl) group. It appears that this step must precede the reduction of ring D, at least by the 'dark' protochlorophyllide reductase enzymes BchN, BchB and BchL [
]. This family appears to be present in photosynthetic bacteria except for the cyanobacterial clade. Cyanobacteria must use a non-orthologous gene to carry out this required step for the biosynthesis of both bacteriochlorophyll and chlorophyll.
In budding yeast (Saccharomyces cerevisiae), SUI1 is a translation initiation
factor that functions in concert with eIF-2 and the initiator tRNA-Met indirecting the ribosome to the proper start site of translation [
]. SUI1 is a protein of 108 residues. Close homologues of SUI1 have been found [] in mammals, insects and plants. SUI1 is also evolutionary related to:Hypothetical proteins from bacteria such as Escherichia coli (yciH) or
Haemophilus influenzae (HI1225).Hypothetical proteins from archaea such as Methanococcus jannaschii
(MJ0463).Two eukaryotic proteins also seem to contain a C-terminal SUI1-like domain.
These are:Density-regulated protein (gene: DENR). This protein is found in mammals,
insects, nematodes, plants and fungi.Ligatin (gene: LGTN). This protein is found in mammals and insects.
In some species, histidine is converted to via urocanate and then formimino-L-glutamate to glutamate in four steps, where the fourth step is conversion of N-formimino-L-glutamate to L-glutamate and formamide. In others, that pathway from formimino-L-glutamate may differ, with the next enzyme being formiminoglutamate hydrolase (HutF) yielding N-formyl-L-glutamate. This entry represents the enzyme N-formylglutamate deformylase, also called N-formylglutamate amidohydrolase, which then produces glutamate [
].
Formylglutamate amidohydrolase (FGase, also known as N-formylglutamate deformylase) catalyses the terminal reaction in the five-step pathway for histidine utilization in Pseudomonas putida. By this action, N-formyl-L-glutamate (FG) is hydrolysed to produce L-glutamate plus formate [
].
Human serum response factor (SRF) is a ubiquitous nuclear protein important for cell proliferation and differentiation. SRF function is essential for transcriptional regulation of numerous growth-factor-inducible genes, such as c-fos oncogene and muscle-specific actin genes. A core domain of around 90 amino acids is sufficient for the activities of DNA-binding, dimerisation and interaction with accessory factors. Within the core is a DNA-binding region, designated the MADS box [
], that is highly similar to many eukaryotic regulatory proteins: among these are MCM1, the regulator of cell type-specific genes in fission yeast; DSRF, a Drosophila trachea development factor; the MEF2 family of myocyte-specific enhancer factors; and the Agamous and Deficiens families of plant homeotic proteins.In SRF, the MADS box has been shown to be involved in DNA-binding and dimerisation [
]. Proteins belonging to the MADS family function as dimers, the primary DNA-binding element of which is an anti-parallel coiled coil of two amphipathic α-helices, one from each subunit. The DNA wraps around the coiled coil allowing the basic N-termini of the helices to fit into the DNA major groove. The chain extending from the helix N-termini reaches over the DNA backbone and penetrates into the minor groove. A 4-stranded, anti-parallel β-sheet packs against the coiled-coil face opposite the DNA and is the central elementof the dimerisation interface.
The MADS-box domain is commonly found associated with K-box region see ().
Proteins in this family belong to the class-II pyridoxal-phosphate-dependent aminotransferase family and may catalyse the transamination reaction in phenylalanine biosynthesis [
].
This entry represents several alpha-2,3-sialyltransferase (
) proteins, most of which are found in the food-borne pathogen Campylobacter jejuni. Sialyltransferases transfer a sialic acid moiety from cytidine-5'-monophospho-N-acetyl-neuraminic acid (CMP-NeuAc) to terminal positions of various key glycoconjugates, which play critical roles in cell recognition and adherence [
]. The structure of Cst-II alpha-2,3-sialyltransferase from C. jejuni consists of a 3-layer alpha/beta/alpha topology. Cst-II catalytic mechanism involves an essential histidine (general base) and two tyrosine residues (coordination of the phosphate leaving group) to carry out substrate binding and glycosyl transfer.
ATP phosphoribosyltransferase (
) is the enzyme that catalyzes the first step in the biosynthesis of histidine in bacteria, fungi and plants as shown below. It is a member of the larger phosphoribosyltransferase superfamily of enzymes which catalyse the condensation of 5-phospho-alpha-D-ribose 1-diphosphate with nitrogenous bases in the presence of divalent metal ions [
].ATP + 5-phospho-alpha-D-ribose 1-diphosphate = 1-(5-phospho-D-ribosyl)-ATP + diphosphate Histidine biosynthesis is an energetically expensive process and ATP phosphoribosyltransferase activity is subject to control at several levels. Transcriptional regulation is based primarily on nutrient conditions and determines the amount of enzyme present in the cell, while feedback inihibition rapidly modulates activity in response to cellular conditions. The enzyme has been shown to be inhibited by 1-(5-phospho-D-ribosyl)-ATP, histidine, ppGpp (a signal associated with adverse environmental conditions) and ADP and AMP (which reflect the overall energy status of the cell). As this pathway of histidine biosynthesis is present only in prokayrotes, plants and fungi, this enzyme is a promising target for the development of novel antimicrobial compounds and herbicides.The ATP phosphoribosyltransferase come in two forms: a long form containing two catalytic domains and a C-terminal regulatory domain, and a short form in which the regulatory domain is missing. The long form is catalytically competent, but in organisms with the short form, a histidyl-tRNA synthetase paralogue, HisZ, is required for enzyme activity [
].The structures of the long form enzymes from Escherichia coli (
) and Mycobacterium tuberculosis (
) have been determined [
,
]. The enzyme itself exists in equilibrium between an active dimeric form, an inactive hexameric form and higher aggregates. Interconversion between the various forms is largely reversible and is influenced by the binding of the natural substrates and inhibitors of the enzyme. The two catalytic domains are linked by a two-stranded β-sheet and togther form a "periplamsic binding protein fold". A crevice between these domains contains the active site. The C-terminal domain is not directly involved in catalysis but appears to be involved the formation of hexamers, induced by the binding of inhibitors such as histidine to the enzyme, thus regulating activity.
This entry represents the short form ATP phosphoribosyltransferases.
Cell division protein ZapB is a non-essential, abundant cell division factor that is required for proper Z-ring formation. It is recruited early to the divisome by direct interaction with FtsZ, stimulating Z-ring assembly and thereby promoting cell division earlier in the cell cycle. Its recruitment to the Z-ring requires functional FtsA or ZipA [
].
Citramalate (also known as 2-methylate) is an intermediate in a large number of biochemical pathways. This entry represents the archaeal citramalate synthase enzyme CimA, which is thought to be involved in isoleucine biosynthesis [
].
Staphylococcus aureus lrgAB operon negatively regulates murein hydrolase activity and promotes tolerance to penicillin [
]. LgrB inhibits the expression or activity of extracellular murein hydrolases by interacting, possibly with LrgA, with the holin-like proteins CidA and/or CidB.
Laminins are glycoproteins that are major constituents of the basement membrane of cells. Laminins are trimeric molecules; laminin-1 is an alpha1 beta1 gamma1 trimer. It has been suggested that the domains I and II from laminin A, B1 and B2 may come together to form a triple helical coiled-coil structure [
]. Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organisation of cells into tissues during embryonic development by interacting with other extracellular matrix components.
This family consists of short proteins predominantly found in Firmicutes, including Uncharacterized protein YqgQ from Bacillus subtilis. YqgQ folds into a three-helical bundle, with the helix order being left-handed and with the third helix flanked by a loop. Based on sequence and structural homology, this protein is thought to be involved in single-stranded nucleic acid binding [
].
Tripeptidyl peptidase II, C-terminal domain, arthropoda
Type:
Domain
Description:
This entry represents the C-terminal domain of tripeptidyl peptidase II (TPPII, MEROPS peptidase family S8A). TPPII is a crucial component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. It is an amino peptidase belonging to the subtilase family removing tripeptides from the free N terminus of oligopeptides [
,
]. It consists of three main parts: the N-terminal subtilisin-like domain (), a central domain (
) and a C-terminal domain [
].
Lipoic acid is an organosulphur compound that is an essential coenzyme in several multienzyme complexes, including pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and the glycine cleavage system. Many Gram-positive bacteria, such as Bacillus subtilis, require three proteins for lipoic acid cofactor biosynthesis: LipJ, LipL and LipM [
,
]. LipM is a lipoate:protein ligase that transfers an octanoyl moiety from acyl-carrier protein to the GcvH protein of the glycine cleavage system. LipL, an octanoyltransferase, then transfers this moiety from GcvH to other enzyme complexes. LipA inserts the sulphur group to form the active lipoate cofactor.This entry represents the LipL component of this system. It includes Lipoyl-[GcvH]:protein N-lipoyltransferase from Listeria monocytogenes serovar 1/2a () [
] and Octanoyl-[GcvH]:protein N-octanoyltransferase (
) from Bacillus subtilis [
].
D-Pantothenate is synthesized via four enzymes from ketoisovalerate, which is an intermediate of branched-chain amino acid synthesis [
]. Pantoate-beta-alanine ligase, also know as pantothenate synthase, (PanC; ) catalyzes the formation of pantothenate from pantoate and alanine in the pantothenate biosynthesis pathway [
].PanC belongs to a large superfamily of nucleotidyltransferases that includes ATP sulfurylase (ATPS), phosphopantetheine adenylyltransferase (PPAT), and the amino-acyl tRNA synthetases. The enzymes of this family are structurally similar and share a dinucleotide-binding domain [
,
,
,
,
].Cytidylate kinase (
) catalyses the phosphorylation of cytidine 5-monophosphate (dCMP) to cytidine 5 -diphosphate (dCDP) in the presence of ATP or GTP. UMP and dCMP can also act as acceptors [
].This entry represents a bifunctional pantoate ligase/cytidylate kinase resulting from a fusion of the individual enzymes. This fusion has so far only been found in cyanobacteria.
This family consists of several short Chordopoxvirus proteins which are homologous to the A30L protein of Vaccinia virus. The vaccinia virus A30L protein is required for the association of electron-dense, granular, proteinaceous material with the concave surfaces of crescent membranes, an early step in viral morphogenesis. A30L is known to interact with the G7L protein and it has been shown that the stability of each is dependent on its association with the other [
].
This family of proteins is found in eukaryotes. Proteins in this family are typically between 107 and 132 amino acids in length. There is a single completely conserved residue H that may be functionally important.
This domain is found in bacteria and eukaryotes, and is approximately 140 amino acids in length. This domain is associated with the phosphatidylserine decarboxylase domain. Proteins containing this domain include PsiD from Psilocybe cubensis. PsiD is a L-tryptophan decarboxylase involved in psilocybin biosynthesis [
].
Lipoic acid is an organosulphur compound that is an essential coenzyme in several multienzyme complexes, including pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and the glycine cleavage system. Many Gram-positive bacteria, such as Bacillus subtilis, require three proteins for lipoic acid cofactor biosynthesis: LipJ, LipL and LipM [
,
]. LipM is a lipoate:protein ligase that transfers an octanoyl moiety from acyl-carrier protein to the GcvH protein of the glycine cleavage system. LipL, an octanoyltransferase, then transfers this moiety from GcvH to other enzyme complexes. LipA inserts the sulphur group to form the active lipoate cofactor.This entry represents the LipM component of this system.
Nitrogen fixation is catalysed by the nitrogenase complex and can be inhibited by carbon monoxide. The CowN protein protects against this inhibition, allowing nitrogen fixation-dependent growth to occur in the presence of carbon monoxide [
]. The mechanism by which CowN confers this protection is not known.
CRISPR (clustered regularly interspaced short palindromic repeats) elements and cas (CRISPR-associated) genes are widespread in Bacteria and Archaea. The CRISPR/Cas system operates as a defense mechanism against mobile genetic elements (i.e., viruses or plasmids). Csa1 is part of the archaeal subtype I-A system. Cas1 has not yet been enzymatically characterised [
].
Autographa californica nuclear polyhedrosis virus (AcMNPV), Protein AC78
Type:
Family
Description:
This entry represents Protein AC78 from Autographa californica nuclear polyhedrosis virus (AcMNPV) and similar proteins from Baculovirus. AC78 is a late gene in the viral life cycle and encodes an envelope structural protein that plays an essential role in embedding the occlusion-derived virus (ODV) in the occlusion body []. Although AC78 is not essential for budding virus formation or nucleocapsid assembly and ODV formation, number are significantly reduced if the gene is knocked-out [].
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].Evidence suggests that, in prokaryotes, the peptidyl transferase reaction is performed by the large subunit 23S rRNA, whereas proteins probably have a greater role in eukaryotic ribosomes. Most of the proteins lie close to, or on the surface of, the 30S subunit, arranged peripherally around the rRNA [
]. The small subunit ribosomal proteins can be categorised as primary binding proteins, which bind directly and independently to 16S rRNA; secondary binding proteins, which display no specific affinity for 16S rRNA, but its assembly is contingent upon the presence of one or more primary binding proteins; and tertiary binding proteins, which require the presence of one or more secondary binding proteins and sometimes other tertiary binding proteins.
The small ribosomal subunit protein S18 is known to be involved in binding the aminoacyl-tRNA complex in Escherichia coli [
], and appears to be situated at the tRNA A-site. Experimental evidence has revealed that S18 is well exposed on the surface of the E. coli ribosome, and is a secondary rRNA binding protein []. S18 belongs to a family of ribosomal proteins [] that includes: eubacterial S18; metazoan mitochondrial S18, algal and plant chloroplast S18; and cyanelle S18.The core structure of S18 is composed of three helices arranged in a close or partly open bundle fold with right-handed twist going up-and down.
A number of actin-binding proteins, including spectrin, alpha-actinin and fimbrin, contain a 250 amino acid stretch called the actin binding domain
(ABD). The ABD has probably arisen from duplication of a domain which is also found in a single copy in a number of other proteins like calponin or the vav proto-oncogene and has been called calponin homology (CH) domain [,
].A detailed analysis of The CH domain-containing proteins has shown that they can be divided in three groups [
]:The fimbrin family of monomeric actin cross-linking molecules containing two ABDsDimeric cross-linking proteins (alpha-actinin, beta-spectrin, filamin, etc.) and monomeric F-actin binding proteins (dystrophin, utrophin) each containing one ABDProteins containing only a single amino terminal CH domain. Each single ABD, comprising two CH domains, is able to bind one actin monomer in the filament. The N-terminal CH domain has the intrinsic ability tobind actin, albeit with lower affinity than the complete ABD, whereas the C-terminal CH bind actin extremely weakly or not at all. Nevertheless
both CH domains are required for a fully functional ABD; the C-terminal CH domain contributing to the overall stability of the complete ABD throughinter-domain helix-helix interactions [
]. Some of the proteins containing a single CH domain also bind to actin, although this has not been shown to be via the single CH domain alone []. In addition, the CH domain occurs also in a number of proteins not known to bind actin, a notable example being the vav protooncogene.The resolution of the 3D structure of various CH domains has shown that the conserved core consist of four major α-helices [
].Proteins containing a calponin domain include:Calponin, which is involved in the regulation of contractility and organisation of the actin cytoskeleton in smooth muscle cells [
].Beta-spectrin, a major component of a submembrane cytoskeletal network connecting actin filaments to integral plasma membrane proteins [
].The actin-cross-linking domain of the fimbrin/plastin family of actin filament bundling or cross-linking proteins [
].Utrophin,a close homologue of dystrophin [
].Dystrophin, the protein found to be defective in Duchenne muscular dystrophy; this protein contains a tandem repeat of two CH domains [
].Actin-binding domain of plectin, a large and widely expressed cytolinker protein [
].The N-terminal microtubule-binding domain of microtubule-associated protein eb1 (end-binding protein), a member of a conserved family of proteins that localise to the plus-ends of microtubules [
].Ras GTPase-activating-like protein rng2, an IQGAP protein that is essential for the assembly of an actomyosin ring during cytokinesis [
].Transgelin, which suppresses androgen receptor transactivation [
].
The PX (phox) domain [
] occurs in a variety of eukaryotic proteins and have been implicated in highly diverse functions such as cell signalling, vesicular trafficking, protein sorting and lipid modification [,
,
,
]. PX domains are important phosphoinositide-binding modules that have varying lipid-binding specificities []. The PX domain is approximately 120 residues long [], and folds into a three-stranded β-sheet followed by three -helices and a proline-rich region that immediately preceeds a membrane-interaction loop and spans approximately eight hydrophobic and polar residues. The PX domain of neutrophil cytosol factor 1 (p47phox) binds to the SH3 domain in the same protein []. Phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), elicits interaction of p47(phox) with phoinositides. The protein phosphorylation-driven conformational change of p47(phox) enables its PX domain to bind to phosphoinositides, the interaction of which plays a crucial role in recruitment of p47(phox) from the cytoplasm to membranes and subsequent activation of the phagocyte oxidase. The lipid-binding activity of this protein is normally suppressed by intramolecular interaction of the PX domain with the C-terminal Src homology 3 (SH3) domain [
].The PX domain is conserved from yeast to human. A multiple alignment of representative PX domain sequences from eukaryotic proteins [
], shows relatively little sequence conservation, although their structure appears to be highly conserved. Although phosphatidylinositol-3-phosphate (PtdIns(3)P) is the primary target of PX domains, binding to phosphatidic acid, phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) has been reported as well. The PX-domain is also a protein-protein interaction domain [].
Carbonic anhydrases (
) (CA) are zinc metalloenzymes which catalyze the reversible hydration of carbon dioxide.
In Escherichia coli, CA (gene cynT) is involved in recycling carbon dioxide formed in the bicarbonate-dependent decomposition of cyanate by cyanase (gene cynS). By this action, it prevents the depletion of cellular bicarbonate []. In photosynthetic bacteria and plant chloroplast, CA is essential to inorganic carbon fixation []. CA has a resolvase-like fold, which has a core structure composed of three layers (alpha/beta/alpha) arranged in mixed β-sheet of five strands where strand 5 is antiparallel to the rest.Prokaryotic and plant chloroplast CA are structurally and evolutionary related and form a superfamily distinct from the one which groups the many different forms of eukaryotic CA's (see
).
This superfamily also includes the Bacillus subtilis protein YbcF that does not seem to be able to bind zinc, which all carbonic anhydrases are thought to require, and a carbon disulfide hydrolase from acidothermophilic archaeon Acidianus, which has a typical carbonic anhydrase fold and active site but does not use CO(2) as a substrate [].
Rhodanese, a sulphurtransferase involved in cyanide detoxification (see
) shares evolutionary relationship with a large family of proteins [
], includingCdc25 phosphatase catalytic domain.non-catalytic domains of eukaryotic dual-specificity MAPK-phosphatases.non-catalytic domains of yeast PTP-type MAPK-phosphatases.non-catalytic domains of yeast Ubp4, Ubp5, Ubp7.non-catalytic domains of mammalian Ubp-Y.Drosophila heat shock protein HSP-67BB.several bacterial cold-shock and phage shock proteins.plant senescence associated proteins.catalytic and non-catalytic domains of rhodanese (see
).
Rhodanese has an internal duplication. This domain is found as a single copy in other proteins, including phosphatases and ubiquitin C-terminal hydrolases [
]. The structure of this domain is composed of three layers (alpha/beta/alpha) arranged in parallel β-sheet of five strands.
During the process of Escherichia coli nucleotide excision repair, DNA damage
recognition and processing are achieved by the action of the uvrA, uvrB,and uvrC gene products [
]. UvrB and UvrC share a common domain of around 35amino acids, the so called UVR domain. This domain in UvrB can interact with
the homologous domain in UvrC throughout a putative coiled coil structure.This interaction is important for the incision of the damaged strand [].A conserved region similar to the UVR domain is also found in the ATP-binding subunit of bacterial and chloroplastic Clp ATPases [
], which suggest that the UVR domain is not only involved in the interaction between uvrB and uvrC.
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [
,
,
,
,
]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few [
]. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. This entry represents the CysCysHisCys (CCHC) type zinc finger domains superfamily, and have the sequence:C-X2-C-X4-H-X4-C
where X can be any amino acid, and number indicates the number of residues. These 18 residues CCHC zinc finger domains are mainly found in the nucleocapsid protein of retroviruses. It is required for viral genome packaging and for early infection process [
,
,
]. It is also found in eukaryotic proteins involved in RNA binding or single-stranded DNA binding [].
The R3H domain superfamily is a conserved sequence motif found in proteins from a diverse range of organisms including eubacteria, green plants, fungi and various groups of metazoans, but not in archaea and Escherichia coli. The domain is named R3H because it contains an invariant arginine and a highly conserved histidine, that are separated by three residues. It also displays a conserved pattern of hydrophobic residues, prolines and glycines. It can be found alone, in association with AAA domain or with various DNA/RNA binding domains like DSRM, KH, G-patch, PHD, DEAD box, or RRM. The functions of these domains indicate that the R3H domain might be involved in polynucleotide-binding, including DNA, RNA and single-stranded DNA [
].The 3D structure of the R3H domain has been solved. The fold presents a small motif, consisting of a three-stranded antiparallel β-sheet, against which two α-helices pack from one side. This fold is related to the structures of the YhhP protein and the C-terminal domain of the translational initiation factor IF3. Three conserved basic residues cluster on the same face of the R3H domain and could play a role in nucleic acid recognition. An extended hydrophobic area at a different site of the molecular surface could act as a protein-binding site [
].
Proteins in this superfamily contains a fold consisted of duplication of β(4)-α-β-α motif. Apart from the beta-lactamases and metallo-beta-lactamases, a number of other proteins also contain this fold [
]. These proteins include thiolesterases, members of the glyoxalase II family, that catalyse the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid and a competence protein that is essential for natural transformation in Neisseria gonorrhoeae and could be a transporter involved in DNA uptake. Except for the competence protein, these proteins bind two zinc ions per molecule as cofactor.
The hsp70 chaperone machine performs many diverse roles in the cell, including folding of nascent proteins, translocation of polypeptides across organelle membranes, coordinating responses to stress, and targeting selected proteins for degradation. DnaJ is a member of the hsp40 family of molecular chaperones, which is also called the J-protein family, the members of which regulate the activity of hsp70s. DnaJ (hsp40) binds to dnaK (hsp70) and stimulates its ATPase activity, generating the ADP-bound state of dnaK, which interacts stably with the polypeptide substrate [
,
]. Structurally, the DnaJ protein consists of an N-terminal conserved domain (called 'J' domain) of about 70 amino acids, a glycine-rich region ('G' domain') of about 30 residues, a central domain containing four repeats of a CXXCXGXG motif ('CRR' domain) and a C-terminal region of 120 to 170 residues.Such a structure is shown in the following schematic representation:
+------------+-+-------+-----+-----------+--------------------------------+
| J-domain | | Gly-R | | CXXCXGXG | C-terminal |+------------+-+-------+-----+-----------+--------------------------------+
The structure of the J-domain has been solved [
]. The J domain consists of four helices, the second of which has a charged surface that includes basic residues that are essential for interaction with the ATPase domain of hsp70 []. J-domains are found in many prokaryotic and eukaryotic proteins [
]. In yeast, three J-like proteins have been identified containing regions closely resembling a J-domain, but lacking the conserved HPD motif - these proteins do not appear to act as molecular chaperones [].
The structure of TusA (also known YhhP and SirA) consists of an α/β sandwich with a β-α-β-α-β(2) fold, comprising a mixed four-stranded β-sheet stacked against two α-helices, both of which are nearly parallel to the strands of the β-sheet [
]. Several uncharacterised bacterial proteins (73 to 81 amino-acid residues in length) that contain a well-conserved region in their N-terminal region show structural similarity to the TusA protein, including the E. coli protein YedF (), and other members of the UPF0033 family.
NOTE: TusA was previously known as SirA, but should not be confused with the sporulation inhibitor of replication protein SirA (
) or with the LuxR/UhpA family response regulator
, also known as SirA.
T-cell immunomodulatory protein (Tip) is a modulator of T-cell function. It has a protective effect in graft versus host disease model [
] and may protect the parasite against attack by the host immune system by immunomodulation [].This entry also includes LINKIN from C. elegans. LINKIN is a transmembrane protein required for maintaining tissue integrity through cell adhesion and apical polarization. It is suggested to be an adhesion molecule that uses its extracellular domain to bind molecules on the surface of neighbouring cells and its intracellular domain to regulate microtubule dynamics [
].
The SERTA (for SEI-1, RBT-1, and TARA) domain is a motif of ~47 residues
corresponding to the largest conserved region among TRIP-Br (transcriptionalregulator interacting with the PHD-bromodomain) proteins, an evolutionarily
conserved family restricted to higher eukaryotes. In proteins of the TRIP-Brfamily, the SERTA domain is found in association with a cyclin A-binding
domain and a PHD-bromo binding domain. The SERTA domain is also found in someother proteins with no conservation with TRIP-Br proteins outside of the SERTA
motif. The cyclin-dependent kinase CDK4-interacting segment of TRIP-Br1includes most of the SERTA domain [
].
This domain family is found in bacteria, and is approximately 190 amino acids in length. The family is found in association with
,
. This family is a bacterial virulence factor - hemolysin - which forms pores in erythrocytes and causes them to lyse.
This entry is represented by Autographa californica nuclear polyhedrosis virus (AcMNPV), Orf29. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.This family consists of several short baculovirus proteins of unknown function.
This family consists of several Adenovirus E3 proteins. The E3 protein does not seem to be essential for virus replication in cultured cells suggesting that the protein may function in virus-host interactions [
].
